Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03154476
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Actual Duration (Months): 23.8
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the medication, sildenafil (also known as Revatio), can slow or stop the progression of liver disease in patients who previously had a Fontan operation.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis; Congenital Heart Disease	Drug: Sildenafil; Drug: Placebo	Phase 3

Detailed Description

1. All participants will undergo a baseline liver magnetic resonance elastography. The patients with liver stiffness score >2.5 kiloPascal (KPa) [Normal: ≤2.5 KPa] will be enrolled in the study.

2. In addition to a baseline liver MRE, all participants will undergo cardiac MRI, transthoracic echocardiogram (TTE), FibroSure® (alpha-2 macroglobulin, haptoglobulin, gamma-glutamyltransferase, bilirubin, apolipoprotein A1, and alanine transaminase), and chemistry panel.

3. This will be a double blinded placebo control study design. All participants will be randomized 1:1 to sildenafil or placebo for a total of 12 months therapy.

4. Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the 3rd week to the end of the study period. The patients will be required to check their pulse rate and blood pressure daily during the first month of drug therapy. Patient who experience hypotension (blood pressure < 90/50 plus symptoms such as dizziness) during dose titration will be asked to remain on the previous tolerated dose. Patients who cannot tolerate 10 mg 3 times daily will be asked to withdraw from the study and will be asked to continue checking their blood pressure for three days after stopping the medication.

5. After 12 months (+/- 2 weeks) of therapy, all imaging studies (liver MRE, cardiac MRI, TTE) and blood tests (FibroSure® and chemistry panel) will be repeated. A final liver MRE and FibroSure will be performed at 18 months (+/- 2 weeks) for the participants whose 18 months follow-up still falls within the study period.

6. Adverse event and compliance monitoring: During the first month of enrollment (initiation and dose titration), adverse events will be collected by subject report and by weekly telephone interview with dedicated research personnel. For the rest of the study period, adverse events will be collected by subject report and by monthly telephone interview with dedicated research personnel. The research personnel will be responsible for sending out the monthly supply of medications and obtaining a count of the remaining number pills as a measure of compliance. All participants will be provided with a pamphlet containing all the side effects of sildenafil, and contact information of research team for reporting any adverse event of concerns about the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized Double-blind Placebo-control studyRandomized Double-blind Placebo-control study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Both the treatment arm (sildenafil) and the placebo arm will receive monthly package of similar pills. Equal number of patients will be randomly assigned to each arm.
• Primary Purpose: Other
• Official Title: Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
• Actual Study Start Date: Jul 5, 2017
• Actual Primary Completion Date: Jun 30, 2019
• Actual Study Completion Date: Jun 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sildenafil Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months.	Drug: Sildenafil; Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months.; Other Names: Revatio
Placebo Comparator: Placebo Subjects will receive placebo times per day for 12 months.	Drug: Placebo; Placebo capsules matching study drug

Outcome Measures

Primary Outcome Measures

1. Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) [Baseline, 12 months (52 weeks), 24 months (104 weeks)]

   Measured using magnetic resonance imaging derived liver stiffness (MRE-LS) reported in kilopascal (kPa).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• All adult Fontan patients who have no contraindications for magnetic resonance imaging (MRI) will be eligible for the study.

Exclusion criteria:

• Subjects with implantable pacemakers

• Residual cardiac lesions (severe ventricular dysfunction, severe atrioventricular valve regurgitation, Fontan baffle or conduit obstruction)

• Viral hepatitis

• Severe renal dysfunction

• History of sildenafil use in the six months prior to study enrollment

• Ongoing sildenafil therapy

• Patients currently taking nitrates

• Hypotension at baseline (BP <90/50 mmHg)

• Pulmonary veno-occlusive disease

• Hearing/vision impairment

• Pulmonary hypertension due to sickle cell disease

• Women of child-bearing potential with a positive pregnancy test will additionally be excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Alexander C Egbe, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 31, 2019

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Alexander C. Egbe, Assistant Professor of Medicine and Pediatrics, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03154476
• Other Study ID Numbers: 16-008985
• First Posted: May 16, 2017
• Last Update Posted: Aug 23, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Liver Diseases; Heart Diseases; Heart Defects, Congenital; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months. Sildenafil: Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months.	Subjects will receive placebo times per day for 12 months. Placebo: Placebo capsules matching study drug
Period Title: Overall Study
STARTED	10	10
COMPLETED	6	6
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Sildenafil	Placebo	Total
Arm/Group Description	Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months. Sildenafil: Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months.	Subjects will receive placebo times per day for 12 months. Placebo: Placebo capsules matching study drug	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28 (6)	29 (5)	29 (5)
Sex: Female, Male (Count of Participants)
Female	3 30%	3 30%	6 30%
Male	7 70%	7 70%	14 70%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE)
Description	Measured using magnetic resonance imaging derived liver stiffness (MRE-LS) reported in kilopascal (kPa).
Time Frame	Baseline, 12 months (52 weeks), 24 months (104 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months. Sildenafil: Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months.	Subjects will receive placebo times per day for 12 months. Placebo: Placebo capsules matching study drug
Measure Participants	6	6
Baseline	5.69 (0.73)	5.72 (0.83)
52 weeks	5.02 (0.94)	5.68 (0.74)
104 weeks	4.67 (0.86)	5.74 (0.84)

Adverse Events

Time Frame	Adverse events were collected from baseline to end of study for a total of approximately 24 months on all participants.
Arm/Group Title	Sildenafil		Placebo
Arm/Group Description	Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months. Sildenafil: Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months.		Subjects will receive placebo times per day for 12 months. Placebo: Placebo capsules matching study drug
All Cause Mortality
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.